Several publications and patent documents are cited in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these citations is incorporated herein by reference.
The worldwide epidemic in obesity has brought with it dramatic increases in the prevalence of co-morbid, chronic conditions including insulin resistance, type 2 diabetes, the metabolic syndrome, and atherosclerosis. The rapid rise in these major public health problems underscores a growing need to understand the physiological and pathological bases of feeding and obesity, and the pathophysiological links between obesity and these associated morbidities.
Kinase Suppressor of Ras (KSR) is a conserved protein that positively regulates Ras signaling and functions as a scaffold for Raf, MEK, and ERK. However, the precise role of KSR is not well understood, and some observations have suggested that KSR might act in a parallel pathway. In C. elegans, ksr-1 is only required for a specific Ras-mediated process (sex myoblast migration) and is a nonessential positive regulator of other Ras-mediated developmental events. A second C. elegans ksr gene, ksr-2 has also been identified, which is required for Ras-mediated signaling during germline meiotic progression and functions redundantly with ksr-1 during development. Thus, while the ksr-1 and ksr-2 genes are individually required only for specific Ras-dependent processes, together these two genes appear necessary for most aspects of Ras-mediated signaling. The finding that ksr-2; ksr-1 double mutants have strong ras-like phenotypes and severely reduced or absent levels of diphosphorylated MPK-1 ERK strongly supports models where KSR acts to promote the activation or maintenance of the Raf/MEK/ERK kinase cascade.
It is an object of the invention to provide a whole animal model for studying these interactions, thereby identifying agents which modulate aberrant processes associated with abnormal KSR2 function. Also provided are cell based systems for the elucidation of the regulatory components in KSR1-KSR2 signaling and the use of such systems to identify small molecules which impact this pathway.